The papillomaviruses are a group of small DNA viruses associated with benign proliferative lesions in a variety of higher vertebrates. A subgroup of viruses are associated with lesions which can progress to malignancy. There are currently 65 different human papillomaviruses and six different bovine papillomaviruses that have been described. The life cycle of these viruses is closely linked to the differentiation program of squamous epithelial cells which are the natural host cell for these viruses. To date, no culture system has yet been developed for the propagation of any papillomaviruses. The bovine papillomavirus type 1 (BPV-l) has served as the prototype of the papillomaviruses for genetic and molecular studies. BPV-l virus readily transforms a variety of rodent cells in tissue culture, and a unique feature of the transformed cells is that the viral DNA often remains as the stable extrachromosomal plasmid within the cells. Our studies have been designed to focus on the molecular biology of the BPV-1 for understanding the normal virus-host cell interaction with the idea of gaining insight into the viral and cellular factors involved in viral gene expression and carcinogenic progression. Within the viral system, the E2 gene products have served as critical factors in regulating viral gene expression. The E2 open reading frame of BPV-1 encodes three distinct proteins with DNA binding properties. These proteins have both negative and positive effects on the regulation of viral gene expression. Our studies have been designed to understand the viral cis-elements and encoded factors involved in transcriptional regulation and replication of the virus.